Citalopram is a well-known antidepressant drug that has now been on the market for some years. Citalopram has the following structure (I):

It is a selective, centrally active serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities. The antidepressant activity of the compound has been reported in several publications, e.g. J. Hyttel, Prog. Neuro-Psychopharmacol. & Biol. Psychiat., 1982, 6, 277-295and A. Gravem, Acta Psychiatr. Scand., 1987, 75,478-486.
Citalopram may be prepared by the process described in U.S. Pat. No. 4,650,884, according to which 5-cyanophthalide is subjected to two successive Grignard reactions, i.e. with 4-fluorophenyl magnesium halogenide and N,N-dimethylaminopropyl magnesium halogenide, respectively, and the resulting compound of the Formula (II) is subjected to a ring closure reaction by dehydration with strong sulfuric acid.

Enantiomers of citalopram may be prepared by the method described in U.S. Pat. No. 4,943,590, i.e. by separating the enantiomers of the intermediate of Formula (II) and performing enantioselective ring closure in order to obtain the desired enantiomer.
Thus, 5-cyanophthalide is an important intermediate for the manufacture of citalopram and escitalopram and it is important to produce this material in an adequate quality, by a convenient process and in a cost-effective way.
A method for the preparation of 5-cyanophthalide has previously been described in Tirouflet, Bull. Soc. Sci. Bretagne, 26, 1951, 35 and in Levy and Stephen, J. Chem. Soc., 1931, 867.
WO 00/39112 describes a method for the preparation of 5-cyanophthalide from 5-carboxyphthalide in which 5-carboxyphthalide is treated with an alcohol R—OH in the presence of an acid to produce an ester corresponding to the compound of Formula (II), i.e. R3 corresponding to R; R is disclosed as C1-6-alkyl or phenyl.

In WO 00/39112 C1-6 alkyl is defined as referring to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl, 2,2-dimethyl-1-ethyl and 2-methyl-1-propyl. In WO 00/39112 is also disclosed the preparation of 5-ethoxycarbonylphthalid by suspension of 5-carboxyphthalide in ethanol, addition of POCl3 followed by heating to reflux temperature for 5 hours. The precipitate was filtered of and washed with ethanol. Similarly, 5-ethoxycarbonylphthalid was prepared by suspension of 5-chlorocarbonylphthalid in ethanol, heating of the mixture to reflux for 15 minutes, followed by cooling, filtration and washing the collected precipitate with ethanol.
Further, WO 00/39112 discloses the conversion of the compound of Formula (III) to an amide having the Formula (IV) by amidation with ammonia or a C1-6-alkylamine, e.g., t-butyl amine; R is H or C1-6 alkyl.

Finally, in WO 00/39112 the amide of Formula (IV) is reacted with a dehydrating agent, e.g. SOCl2, thereby obtaining 5-cyanophthalide having the Formula (V).

JP 62185070 A2 describes use of phthalimides for treatment of angina pectoris.
A further method for the preparation of 5-cyanophthalide from 5-carboxyphthalide is described in WO 00/044738. Reference is also made to WO 98/19513 and WO 98/19511 describing methods for the preparation of citalopram.
The preparation of 5-carboxyphthalide of Formula (VI) from terephthalic acid of Formula (VII) is described in, e.g., U.S. Pat. Nos. 6,403,813, 6,458,973, 3,607,884 and by Forney, L. S, J. Org. Chem. 1970, 35, p. 1695-1696.

Accordingly, U.S. Pat. No. 3,607,884 discloses a method of producing 5-carboxyphthalide by reaction of terephthalic acid with formaldehyde and SO3, followed by addition of water. U.S. Pat. No. 3,607,884 also discloses a reaction of formaldehyde with terephthalic acid and SO3 which is cooled down and poured into alcohol (e.g. methanol or ethanol); it is stated that thereby the corresponding ester of 5-carboxypthalide is produced and that this ester subsequently can be converted to 5-carboxyphthalide. Forney, L. S, J. Org. Chem. 1970, 35, p. 1695-1696 and U.S. Pat. No. 3,607,884 further discloses the preparation of 5-methoxycarbonylphtalide and 5-ethoxycarbonylphtalide by esterification of 5-carboxyphthalide. Another method is described by Anzalone L. and Hirsch J. A, J. Org. Chem. 1985, 50, 2128-2133 in which an ester substituted phthalide is prepared from diethyl 2-methylterepthalate.
Forney, L. S, J. Org. Chem. 1970, 35, p. 1695-1696 discloses a reaction of terephthalic acid (Formula VII), trioxane, and sulfuric acid by heating to 150° C. for 2 hours in a sealed glass tube; the tube was chilled and opened and the content poured into methanol, concentrated, poured into water, and extracted into dichloromethane. The yield of this reaction is disclosed as 83.2% dimethyl terephthalate and 1.1% 5-methoxycarbonylphtalide.
Furthermore, a reaction of oleum, terephthalic acid and formaldehyde is also disclosed in Forney, L. S, J. Org. Chem. 1971, 36, p. 689-693. WO9916743 discloses compounds with alkoxycarbonyl groups, among which are compounds corresponding to formula III.
Sugimori, A. and Yashima, T, Chemistry Letters, 1980, 483-486, describes gamma-radiation of aromatic carboxylic esters in alcohol solutions, exemplified by radiation of dimethyl terephthalate. In this connection is disclosed a formula corresponding to the compound of formula (III) wherein R3 is methyl. Similarly, Anzalone L. and Hirsch J. A., J. Org. Chem 1985, 2128-2133 describes the preparation of a compound corresponding to formula (III) wherein R3 is ethyl from diethyl 2-methylterepthtalate.
One aspect of the invention provides a new method for the preparation of 5-cyanophthalide without the need for 5-carboxyphthalide.